Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome.

摘要: This research explores the first design and synthesis of macrocyclic peptide aldehydes as potent inhibitors 20S proteasome. Two novel based on ring-size natural product TMC-95 were prepared evaluated Both compounds inhibited in low nanomolar range proved to be selective for proteasome over other serine cysteine proteases, particularly when compared linear analogues with similar amino acid sequences. In HeLa cells, both macrocycles efficiently activation nuclear factor-κB (NF-κB) transcription factor by blocking proteasomal degradation inhibitor protein IκBα after cytokine stimulation. Due their covalent mechanism binding these represent a 1000-fold increase inhibitory potency previously reported noncovalently analogues. Molecular modeling peptides confirms preference large S3 pocket large, hydrophobic residues ability exploit this improve selectivity inhibitors.